The present invention relates to pyrazolopyridines and imidazopyridines which are inhibitors of the kinase PDK1 and are thus useful for the treatment of myeloproliferative disorders or cancer. The compounds are also useful as inhibitors of other kinases such as FGFR3, NTRK3, RP-S6K and WEE1. Furthermore, the present compounds also selectively inhibit microtubule affinity regulating kinase (MARK) and are therefore useful for the treatment or prevention of Alzheimer's disease.
PDK1
PDK1 is a Ser/Thr protein kinase possessing a kinase domain at its N-terminus (residues 70-359) and a Pleckstrin homology (PH) domain at its C-terminus (residues 459-550). The kinase can phosphorylate and activate a number of kinases in the AGC kinase superfamily, including Akt/protein kinase B, protein kinase C(PKC), PKC-related kinases (PRK1 and PRK2), p70 ribobsomal S6-kinase (S6K1) and serum and glucocorticoid-regulated kinase (SGK). Akt comprises a family of Ser/Thr protein kinases containing three highly homologous members (AKT1, AKT2 and AKT3) and its activation in cells by PDK1 requires stimulation of phosphoinositide 3-kinase (PI 3-kinase) (Feldman, Richard I., et al., The Journal of Biological Chemistry, Vol. 280, No. 20, Issue of May 20, pp. 19867-19874, 2005). The activation of Akt in tumor cells has been shown to have multiple upstream effects that promote disease progression, including suppression of apoptosis and stimulation of tumor cell proliferation, metabolism and angiogenesis. Thus the PI 3-kinase/PDK1/Akt signaling pathway plays a key role in regulating cancer cell growth, invasion, apoptosis and tumor angiogenesis. Furthermore, this pathway has been found to be highly activated in common cancers, including melanoma and haematological, breast, colon, pancreatic, prostate and ovarian cancers (Feldman, Richard I., et al, supra). The PI 3-kinase/PDK1/Akt signaling pathway is therefore a useful target for the developments of anticancer agents.
FGFR3
The Tec family kinase, Bmx, a non-receptor protein-tyrosine kinase, controls the proliferation of mammary epithelial cancer cells. Fibroblast growth factor receptor 3 (FGFR3) has been shown to exert a negative regulatory effect on bone growth and on inhibition of chondrocyte proliferation. Thanatophoric dysplasia is caused by different mutations in fibroblast growth factor receptor 3, and one mutation, TDII FGFR3, has a constitutive tyrosine kinase activity which activates the transcription factor Stat1, leading to expression of a cell-cycle inhibitor, growth arrest and abnormal bone development (Su et al., Nature, 1997, 386, 288-292). FGFR3 is also often expressed in multiple myeloma-type cancers. Inhibitors of FGFR3 activity are useful in the treatment of T-cell mediated inflammatory or autoimmune diseases including but not limited to rheumatoid arthritis (RA), collagen II arthritis, multiple sclerosis (MS), systemic lupus erythematosus (SLE), psoriasis, juvenile onset diabetes, Sjogren's disease, thyroid disease, sarcoidosis, autoimmune uveitis, inflammatory bowel disease (Crohn's and ulcerative colitis), celiac disease and myasthenia gravis.
NTRK3
NTRK3 (TRKC) is a member of the trk family of neurotrophin receptors and is able to control tumor cell growth and survival as well as differentiation, migration and metastasis. NTRK3 and its closely related family members NTRK1 (TRKA) and NTRK2 (TRKB) are implicated in the development and progression of cancer, possibly by upregulation of either the receptor, their ligand (Nerve Growth Factor, Brain Derived Neurotrophic Factor, Neurotrophins) or both. High expression of NTRK2 and/or its ligand BDNF has been shown in pancreatic and prostate carcinomas, WiIm's tumors and neuroblastomas. In addition, high expression of NTRK3 is a hallmark of Melanoma, especially in cases with brain metastasis. In many cases high Trk expression is associated with aggressive tumor behaviour, poor prognosis and metastasis.
Genetic abnormalities, i.e. point mutations and chromosomal rearrangements involving both NTRK2 and NTRK3 have been found in a variety of cancer types. In a kinome-wide approach to identify point mutants in tyrosine kinases both NTRK2 and NTRK3 mutations were found in cell lines and primary samples from patients with colorectal cancer (Manning et al., 2002, Bardelli et al., 2003). In addition, chromosomal translocations involving both NTRK1 and NTRK3 have been found in several different types of tumors. Moreover, secretary breast cancer, infant fibrosarcoma and congenital mesoblastic nephroma have been shown to be associated with a chromosomal rearrangement t(12; 15) generating a ETV6-NTRK3 fusion gene that was shown to have constitutive kinase activity and transforming potential in several different cell lines including fibroblasts, hematopoietic cells and breast epithelial cells.
RP-S6K
The ribosomal protein S6 kinase (RP-S6K/p70S6K1) is a serine/threonine kinase implicated in the development and progression of cancer. Thus, compounds which inhibit the action of this kinase are useful as anti-cancer agents.
WEE1
Cells have a checkpoint mechanism of such that, when the DNA therein is damaged, then the cells temporarily stop the cell cycle and repair the damaged DNA (Cell Proliferation, Vol. 33, pp. 261-274). In about a half of human cancers, a cancer-suppressor gene, p53 is mutated or depleted and the cells thereby have lost the G1 checkpoint function thereof. However, such cancer cells still keep the G2 checkpoint function remaining therein, which is considered to be one factor of lowering the sensitivity of the cells to DNA-active anticancer agents and to radiations.
A Wee1 kinase is a tyrosine kinase that participates in the G2 checkpoint of a cell cycle. Wee1 phosphorylates Cdc2(Cdk1) tyrosine 15 that participates in the progress to the M stage from the G2 stage in a cell cycle, thereby inactivating Cdc2 and temporarily stopping the cell cycle at the G2 stage (Tfie EMBO Journal, Vol. 12, pp. 75-85). Accordingly, in cancer cells having lost the p53 function therein, it is considered that the G2 checkpoint function by Wee1 is important for repairing the damaged DNA so as to evade the cell death. Heretofore, it has been reported that the Wee1 expression reduction by RNA interference or the Wee1 inhibition by compounds may increase the sensitivity of cancer cells to adriamycin, X ray and gamma ray (Cancer Biology & Therapy, Vol. 3, pp. 305-313; Cancer Research, Vol. 61, pp. 8211-8217). From the above, it is considered that a Wee1 inhibitor may inhibit the G2 checkpoint function of p53-depleted cancer cells, thereby enhancing the sensitivity of the cells to DNA-active anticancer agents and to radiations. Wee1 inhibitors are therefore suitable for the treatment of tumor diseases, such as gliomas, sarcomas, prostate tumors, and tumors of the colon, breast, and ovary.
MARK
The classic clinical and neuropathological features of AD consist of senile or neuritic plaques and tangled bundles of fibers (neurofibrillary tangles) [Verdile, G., et al, Pharm. Res. 50:397-409 (2004)]. In addition, there is a severe loss of neurons in the hippocampus and the cerebral cortex. Neuritic plaques are extracellular lesions, consisting mainly of deposits of β-amyloid peptide (Aβ), surrounded by dystrophic (swollen, damaged and degenerating) neurites and glial cells activated by inflammatory processes. In contrast, neurofibrillary tangles (NFTs) are intracellular clusters composed of a hyperphosphorylated form of the protein tau, which are found extensively in the brain (e.g. mainly in cortex and hippocampus in AD). Tau is a soluble cytoplasmic protein which has a role in microtubule stabilisation. Excessive phosphorylation of this protein renders it insoluble and leads to its aggregation into paired helical filaments, which in turn form NFTs.
The microtubule affinity-regulating kinase (MARK) is part of the AMP-dependent protein kinase (AMPK) family and exists in four isoforms. MARK is thought to phosphorylate tau to result in an unbound, hyperphosphorylated tau which is delocalised to the somatodendritic compartment and then cleaved by caspases to form fragments prone to aggregation [Drewes, G. (2004). Trends Biochem. Sci 29:548-555; Gamblin, T. C., et al, (2003) Proc. Natl. Acad. Sci. U.S.A. 100:10032-10037]. These aggregates can grow into filaments, which are potentially toxic, eventually forming the NFTs found in AD.
Thus, MARK inhibitors are useful for preventing or ameliorating neurodegeneration in AD and other tauopathies.
The instant invention provides compounds which inhibit the activity of the PDK1 kinase and/or other kinases such as FGFR3, NTRK3, RP-S6K and/or WEE1. The compounds also inhibit the activity of the microtubule affinity regulating kinase (MARK). The present invention provides compounds of formula I:
wherein:
either X and Y are both N and Z is C, or X and Z are both N and Y is C;
L1 is a direct bond, —(C≡C)a(C═O)b(NRc)c(CRaRb)d(NRc)c(C═O)b— or —(CRa-Rb)d(C═O)b(NRc)c(CRaRb)d—;
a is 1 or 2;
b is 0 or 1;
c is 0 or 1;
d is 0, 1, 2, 3, 4, 5 or 6;
L2 is —O(CRaRb)d— or —(NRc)(C═O)b—;
L3 is a direct bond, —C≡C— or —(HC═CH)e(CRaRb)d(NRc)c—;
e is 0 or 1;
R1 is hydrogen, hydroxy, cyano, halogen, C1-6alkyl, C2-10alkenyl, haloC1-6alkyl, hydroxyC1-6alkyl, C1-6alkylcarbonyl, C1-6alkoxy, haloC1-6alkoxy, C1-6alkoxycarbonyl, carboxy, nitro, N(Rx)2, SO2Rx, Si(Rx)3 or a ring which is: C6-10aryl, C3-10cycloalkyl, azetidinyl, a 5 or 6 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 atoms independently selected from N, O and S, a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, and S, not more than one heteroatom of which is O or S, a 6 membered heteroaromatic ring containing 1, 2 or 3 N atoms or a 7-15 membered unsaturated, partially saturated or saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; optionally substituted by one, two or three groups independently selected from L4-Rd;
R2 is selected from hydroxy, cyano, halogen, C1-6alkyl, C2-10alkenyl, haloC1-6alkyl, hydroxyC1-6alkyl, C1-6alkylcarbonyl, C1-6alkoxy, haloC1-alkoxy, C1-6alkoxycarbonyl, carboxy, nitro, N(Rx)2 or a ring which is: C6-10aryl, C3-10cycloalkyl, azetidinyl, a 5 or 6 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 atoms independently selected from N, O and S, a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S, a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms or a 7-15 membered unsaturated, partially saturated or saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; any of which rings being optionally substituted by one, two or three groups independently selected from Re;
R3 is selected from hydrogen, hydroxy, cyano, halogen, C1-6alkyl, C2-10alkenyl, haloC1-6alkyl, hydroxyC1-6alkyl, C1-6alkylcarbonyl, C1-6alkoxy, haloC1-alkoxy, C1-6alkoxycarbonyl, carboxy, nitro, N(Rx)2 or a ring which is: C6-10aryl, C6-10arylC1-6alkyl, C3-10cycloalkyl, azetidinyl, a 5 or 6 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 atoms independently selected from N, O and S, a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S, a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms or a 7-15 membered unsaturated, partially saturated or saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; any of which rings being optionally substituted by one, two or three groups independently selected hydroxy, cyano, halogen, C1-6alkyl, C2-10alkenyl, haloC1-6alkyl and hydroxyC1-6alkyl;
R4 is selected from hydrogen, hydroxy, cyano, halogen, C1-6alkyl, C2-10alkenyl, haloC1-6alkyl, hydroxyC1-6alkyl, C1-6alkylcarbonyl, C1-6alkoxy, haloC1-alkoxy, C1-6alkoxycarbonyl, carboxy, nitro, N(Rx)2 or a ring which is: C6-10aryl, C6-10arylC1-6alkyl, C3-10cycloalkyl, azetidinyl, a 5 or 6 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 atoms independently selected from N, O and S, a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S, a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms or a 7-15 membered unsaturated, partially saturated or saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; any of which rings being optionally substituted by one, two or three groups independently selected from L5-Rf;
R5 is hydrogen, hydroxy, cyano, halogen, C1-6alkyl, C2-10alkenyl, haloC1-6alkyl, hydroxyC1-6alkyl, C1-6alkylcarbonyl, C1-6alkoxy, haloC1-alkoxy, C1-6alkoxycarbonyl, carboxy, nitro or N(Rx)2;
L4 is a direct bond, —(CRaRb)d(C═O)b(NRc)c(C═O)b(O)g(CRaRb)d(NRc)c— or —(NRc)c(SO2)f(NRc)c(CRaRb)d;
L5 is a direct bond or —(C═O)b(NRc)c(C═O)b(CRaRb)d—;
f is 0 or 1;
g is 0 or 1;
each of Ra and Rb is independently hydrogen, hydroxy, halogen, C1-6alkyl, C2-10alkenyl, haloC1-6alkyl, hydroxyC1-6alkyl, C1-6alkoxy or haloC1-6alkoxy;
Rc is hydrogen or C1-6alkyl;
Rd is hydroxy, oxo, cyano, halogen, C1-6alkyl, C2-10alkenyl, haloC1-6alkyl, hydroxyC1-6alkyl, C1-6alkylcarbonyl, C1-6alkoxy, haloC1-6alkoxy, amino, (C1-6alkyl)amino, di(C1-6alkyl)amino or a ring which is: C6-10aryl, C3-10cycloalkyl, azetidinyl, a 5, 6 or 7 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 atoms independently selected from N, O and S, a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, and S, not more than one heteroatom of which is O or S or a 6 membered heteroaromatic ring containing 1, 2 or 3 N atoms; any of which rings being optionally substituted by one, two or three groups independently selected from hydroxy, oxo, cyano, halogen, C1-6alkyl, C2-10alkenyl, hydroxyC1-6alkyl, C1-6alkylcarbonyl, C1-6alkoxy, haloC1-alkoxy, C1-6alkoxycarbonyl, carboxy, nitro, amino, (C1-6alkyl)amino and di(C1-6alkyl)amino;
Re is hydroxy, cyano, halogen, C1-6alkyl, C2-10alkenyl, hydroxyC1-6alkyl, C1-6alkylcarbonyl, C1-6alkoxy, haloC1-6alkoxy, C1-6alkoxycarbonyl, carboxy, or SO2Rx;
Rf is hydroxy, oxo, cyano, halogen, C1-6alkyl, C2-40alkenyl, hydroxyC1-6alkyl, C1-6alkylcarbonyl, C1-6alkoxy, haloC1-6alkoxy or a ring which is: C6-10aryl, C3-10cycloalkyl, azetidinyl, a 5, 6 or 7 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 atoms independently selected from N, O and S, a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, and S, not more than one heteroatom of which is O or S or a 6 membered heteroaromatic ring containing 1, 2 or 3 N atoms; any of which rings being optionally substituted by one, two or three groups independently selected from hydroxy, oxo, cyano, halogen, C1-6alkyl, C2-10alkenyl, haloC1-6alkyl, hydroxyC1-6alkyl, C1-6alkylcarbonyl, C1-6alkoxy, haloC1-alkoxy, C1-6alkoxycarbonyl, carboxy, nitro, amino, (C1-6alkyl)amino and di(C1-6alkyl)amino;
each of Rx and Ry is independently hydrogen or C1-6alkyl;
or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.
In an embodiment a is 1.
In an embodiment b is 0. In another embodiment b is 1.
In an embodiment c is 0. In another embodiment c is 1.
In an embodiment d is 0, 1, 2 or 3.
In an embodiment L1 is a direct bond.
In another embodiment L1 is —(C≡C)a(C═O)b(NRc)c(CRaRb)d(NRc)c(C═O)b—.
In an embodiment L1 is —(C≡C)—.
In an embodiment a is 1.
In another embodiment L1 is —(CRaRb)d(C═O)b(NRc)c(CRaRb)d—.
Particular L1 groups are a direct bond, —(C═O)—, —(C≡C)—, —(C≡C)(CRaRb)—, —(C≡C)(C═O)NRc—, —(C≡C)(CRaRb)2NRc—, —(C≡C)2—, —(CRaRb)—, —(CRaRb)NRc—, —(CRaRb)NRc(CRaRb)2—, —(CRaRb)NRc(CRaRb)—, —NRc(CRaRb)2—, —NRc—, —NRc(CRaRb)3—, —(C═O)NRc—, —(C═O)NH(CRaRb)2—, —(C═O)NRc(CRaRb)—, —(C═O)NRc(CRaRb)3—, —(CRaRb)2—, —(C═O)(CRaRb)—, —(C≡C)(CRaRb)NRc—, —(C≡C)(CRaRb)— and —(C≡C)(CRaRb)NRc(C═O—.
Specific L1 groups are a direct bond, —(C═O)—, —(C≡C)—, —(C≡C)(CH2)—, —(C≡C)(C═O)NH—, —(C≡C)(CH2)2NH—, —(C≡C)2—, —(CH2)—, —CH2NH—, —CH2NH(CH2)2—, —CH2NHCH2—, —NH(CH2)—, —NH(CH2)2—, —NH—, —NH(CH2)3—, —(C═O)NH—, —(C═O)NH(CH2)2—, —(C═O)NH(CH2)—, —(C═O)NH(CH2)3—, —(CH2)2—, —(C═O)(CH2)—, —(C≡C)(CH2)NH—, —(C≡C)(CHOH)— and —(C≡C)(CH2)NH(C═O)—.
In an embodiment R1 is hydrogen, hydroxy, cyano, halogen, C1-6alkyl, haloC1-6alkyl, hydroxyC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, N(Rx)2, SO2Rx or Si(Rx)3 or a ring which is: C6-10aryl, C3-10cycloalkyl, azetidinyl, a 5 or 6 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 atoms independently selected from N, O and S, a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, and S, not more than one heteroatom of which is O or S, a 6 membered heteroaromatic ring containing 1, 2 or 3 N atoms or a 7-10 membered unsaturated, partially saturated or saturated heterocyclic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S; any of which rings being optionally substituted by one, two or three groups independently selected from L4-Rd;
In an embodiment R1 is hydrogen, cyano, methoxy, iodine, chlorine, bromine, trimethylsilyl, hydroxy, methylsulfonyl, dimethylamino, methyl, ethyl, amino or a ring selected from: pyridinyl, cyclopropyl, pyrazolyl, phenyl, imidazolyl, pyrrolidinyl, azetidinyl, piperidinyl, isoxazolyl, thiazolyl, pyrrolyl, imidazopyridinyl, pyrazolopyridinyl, imidazopyrazinyl, thiadiazolyl, tetrahydroimidazopyridinyl, dihydrotriazolopyrazinyl, diazaspiro[3.5]nonyl, diazaspiro[3.3]heptyl, pyrazinyl, pyridazinyl, indazolyl, benzimidazolyl, dihydrobenzimidazolyl, indolyl, pyrimidinyl, morpholinyl, benzothienyl, cyclopentyl, quinolinyl, thienyl, isothiazolyl, naphthyridinyl, quinazolinyl and triazolyl; any of which rings being optionally substituted by one, two or three groups independently selected from L4-Rd.
In an embodiment L4 is a direct bond.
In another embodiment L4 is —(CRaRb)d(C═O)b(NRc)c(C═O)b(O)g(CRaRb)d(NRc)c—.
In another embodiment L4 is —(NRc)c(SO2)f(NRc)c.
In an embodiment L4 is a direct bond, —N(Rc)(C═O)—, —(C═O)—, —SO2N(Rc)—, —CRaRb—, —SO2—, —N(Rc)(SO2)—, —(CRaRb)(C═O), (C═O)N(Rc)(CRaRb)—, —(C═O)N(Rc)—, —(C═O)N(Rc)(CRaRb)2—, —(C═O)N(Rc)(CRaRb)3—, —N(Rc)(C═O)N(Rc)—, —(C═O)(O)(CRaRb)—, —(CRaRb)2—, —(CRaRb)N(Rc)— or —SO2N(Rc)(CRaRb)—.
Specific L4 groups are a direct bond, —NH(C═O)—, —(C═O)—, —SO2N(CH3)—, —CH2—, —SO2—, —C(OH)H—, —NH(SO2)—, —CH2(C═O)—, —(C═O)NH(CH2)—, —(C═O)NH—, —(C═O)NH(CH2)2—, —(C═O)NH(CH2)3—, —NH(C═O)NH, —(C═O)(O)(CH2)—, —(CH2)2—, —(CH2)NH— and —SO2NH(CH2)—.
In an embodiment Rd is hydroxy, oxo, cyano, halogen, C1-6alkyl, haloC1-6alkyl, hydroxyC1-6alkyl, C1-6alkylcarbonyl, C1-6alkoxy, haloC1-6alkoxy, amino, (C1-6alkyl)amino, di(C1-6alkyl)amino or a ring which is: C6-10aryl, C3-10cycloalkyl, azetidinyl, a 5, 6 or 7 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 atoms independently selected from N, O and S, a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, and S, not more than one heteroatom of which is O or S or a 6 membered heteroaromatic ring containing 1, 2 or 3 N atoms; any of which rings being optionally substituted by one, two or three groups independently selected from hydroxy, oxo, cyano, halogen, C1-6alkyl, C2-10alkenyl, haloC1-6alkyl, hydroxyC1-6alkyl, C1-6alkylcarbonyl, C1-6alkoxy, haloC1-alkoxy, C1-6alkoxycarbonyl, carboxy, nitro, amino, (C1-6alkyl)amino and di(C1-6alkyl)amino.
In an embodiment when Rd is a ring it is optionally substituted by one or two independently selected groups. In another embodiment the Rd ring is unsubstituted or monosubstituted.
In an embodiment the optional substituents on the Rd ring are selected from halogen, oxo, C1-6alkyl, C1-6alkoxy, amino, C1-6alkylamino and diC1-6alkylamino.
Particular optional substitutents on the Rd ring are methyl, fluorine, chlorine, tertbutyl, methoxy, amino and oxo.
In an embodiment Rd is methyl, methoxy, tertbutoxy, amino, hydroxy, chlorine, fluorine, tertbutyl, ethyl, trifluoromethyl, bromine, cyano, oxo, isopropyl, fluoromethyl, acetyl, ethylamino or a ring selected from: cyclopropyl, phenyl, pyridinyl, pyrrolidinyl, pyrazolyl, cyclohexyl, piperazinyl, thienyl, thiazolyl, cyclobutyl, tetrahydrofuranyl, furyl, cyclopentyl, isoxazolyl, thiazolyl and morpholinyl; the ring being optionally substituted as defined above.
Particular Rd groups are methyl, phenyl, pyridinyl, methoxy, tertbutoxy, amino, pyrrolidinyl, hydroxy, chlorine, fluorine, methylpyrazolyl, tertbutyl, cyclopropyl, ethyl, fluorophenyl, chlorophenyl, tertbutylphenyl, methylphenyl, methoxyphenyl, trifluoromethyl, bromine, cyano, oxo, aminocyclohexyl, piperazinyl, oxopyrrolidinyl, thienyl, dimethylthiazolyl, dimethylphenyl, isopropyl, cyclobutyl, tetrahydrofuranyl, furyl, cyclopentyl, fluoromethyl, methylisoxazolyl, methylthiazolyl, dimethylpyrazolyl, morpholinyl, dimethylisoxazolyl, fluoropyridinyl, acetyl and ethylamino.
Specific Rd groups are methyl, phenyl, pyridin-2-yl, methoxy, tertbutoxy, amino, pyrrolidin-1-yl, hydroxy, chlorine, fluorine, 1-methyl-1H-pyrazol-4-yl, tertbutyl, cyclopropyl, ethyl, 2-fluorophenyl, 4-chlorophenyl, 4-tertbutylphenyl, 4-fluorophenyl, 2-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, pyridin-3-yl, trifluoromethyl, bromine, cyano, oxo, (1S,2R)-2-aminocyclohexyl, (1S,2S)-2-aminocyclohexyl, piperazin-1-yl, 2-oxopyrrolidin-1-yl, 2-thienyl, 3-chlorophenyl, 3-fluorophenyl, 2-methoxyphenyl, 4,5-dimethyl-1,3-thiazol-2-yl, 2,6-dimethylphenyl, isopropyl, cyclobutyl, 3-thienyl, tetrahydrofuran-3-yl, 3-furyl, cyclopentyl, fluoromethyl, 5-methylisoxazol-3-yl, 2-furyl, 4-methyl-1,3-thiazol-2-yl, 2-methyl-1,3-thiazol-4-yl, 2-methylphenyl, 3,5-dimethyl-1H-pyrazol-4-yl, morpholin-4-yl, 3,5-dimethylisoxazol-4-yl, 2-fluoropyridin-3-yl, pyridin-4-yl, acetyl and ethylamino.
Particular R1 groups are hydrogen, cyano, methoxy, iodine, chlorine, bromine, pyridinyl, cyclopropyl, (methyl)(phenyl)pyrazolyl, (methyl)(pyridinyl)pyrazolyl, trimethylsilyl, methoxyphenyl, hydroxy, methylimidazolyl, (acetylamino)phenyl, methylsulfonyl, (tertbutoxycarbonyl)pyrrolidinyl, aminopyridinyl, (tertbutoxycarbonyl)azetidinyl, (tertbutoxycarbonyl)piperidinyl, pyrrolidinylpyridinyl, acetylphenyl, hydroxyphenyl, dimethylpyrazolyl, dimethylisoxazolyl, [(dimethylamino)sulfonyl]imidazolyl, methylpyrazolyl, (aminocarbonyl)pyridinyl, methoxypyridinyl, hydroxypyridinyl, chloropyridinyl, fluoropyridinyl, aminothiazolyl, (acetylamino)pyridinyl, thiazolyl, methylisoxazolyl, imidazolyl, trimethylpyrazolyl, (tertbutoxycarbonyl)pyrazolyl, pyrazolyl, benzylpyrazolyl, azetidinyl, pyrrolidinyl, (methoxycarbonyl)pyrrolyl, imidazopyridinyl, (methoxy)(methylpyrazolyl)pyrazolopyridinyl, (amino)(methyl)pyrazolyl, imidazopyrazinyl, (tertbutyl)thiadiazolyl, (methyl)thiadiazolyl, cyclopropylthiadiazolyl, tetrahydroimidazopyridinyl, ethylthiadiazolyl, (tertbutoxycarbonyl)dihydrotriazolopyrazinyl, (acetylamino)thiazolyl, methylimidazopyridinyl, (methyl)(phenyl)imidazolyl, (fluorophenyl)(methyl)pyrazolyl, (chlorophenyl)(methyl)pyrazolyl, (tertbutylphenyl)(methyl)pyrazolyl, (fluorophenyl)(methyl)pyrazolyl, (chlorophenyl)(methyl)pyrazolyl, dimethylimidazolyl, phenylpyrazolyl, dimethylpyrazolyl, (methyl)(methylphenyl)pyrazolyl, (methoxyphenyl)(methyl)pyrazolyl, (methyl)(pyridinyl)pyrazolyl, diazaspiro[3.5]nonyl, diazaspiro[3.3]heptyl, (carboxy)(methyl)phenyl, (trifluoromethyl)pyridinyl, bromopyridinyl, cyanopyridinyl, (acetylamino)phenyl, pyrazinyl, pyridazinyl, hydroxypyridinyl, aminophenyl, indazolyl, benzimidazolyl, oxodihydrobenzimidazolyl, indolyl, methylpyridinyl, pyrimidinyl, thiadiazolyl, phenyl, morpholinyl, dimethylamino, bromobenzothienyl, dimethylpyridinyl, (acetylamino)phenyl, methyl, benzylpyrrolidinyl, (hydroxymethyl)cyclopentyl, (ethylsulfonyl)(hydroxy)phenyl, methoxyquinolinyl, (cylopropyl)(methyl)pyrazolyl, (aminocarbonyl)(ethyl)pyrazolyl, (trifluoroacetyl)azetidinyl, ethyl, cyclopentyl, (trifluoromethyl)phenyl, chlorophenyl, thienyl, cyanophenyl, fluorophenyl, methylphenyl, difluorophenyl, amino, [(methylsulfonyl)amino]phenyl, {[(aminocyclohexyl)amino]carbonyl}thienyl, (methoxycarbonyl)phenyl, (aminocarbonyl)phenyl, [(aminocarbonyl)methyl]pyrazolyl, (methoxycarbonyl)thienyl, carboxythienyl, [(aminocyclohexyl)amino]carbonylthienyl, (aminocarbonyl)thienyl, pyrrolyl, {[(trifluoroethyl)amino]carbonyl}thienyl, {[(aminoethyl)amino]carbonyl}thienyl, (piperazinylcarbonyl)thienyl, ({[(oxopyrrolidinyl)propyl]amino}carbonyl)thienyl, isothiazolyl, aminocarbonylpyrrolyl, (dimethyl)(phenyl)pyrazolyl, (ethyl)(phenyl)pyrazolyl, (cyclopropyl)(phenyl)pyrazolyl, (methyl)(thienyl)pyrazolyl, [(methoxyphenyl)sulfonylamino]pyridinyl, {[(phenylamino)carbonyl]amino}pyridinyl, [(pyridinylmethyl)methoxycarbonyl]azetidinyl, (dimethylthiazolyl)(methyl)pyrazolyl, (dimethylphenyl)(methyl)pyrazolyl, (tertbutyl)(phenyl)pyrazolyl, (isopropyl)(phenyl)pyrazolyl, (cyclobutyl)(phenyl)pyrazolyl, (methyl)(methylpyrazolyl)pyrazolyl, pyrrolidinyl, pyridinylthiadiazolyl, (methyl)(thienyl)imidazolyl, (methoxyethyl)(methyl)imidazolyl, (isopropyl)(methyl)imidazolyl, (cyclobutyl)(methyl)imidazolyl, (methyl)(tetrahydrofuranyl)imidazolyl, (furyl)(methyl)imidazolyl, (cyclopentyl)(methyl)imidazolyl, (fluoromethyl)(methyl)imidazolyl, (methyl)(methylisoxazolyl)imidazolyl, (methyl)(pyridinyl)imidazolyl, (methyl)(methylthiazolyl)imidazolyl, naphthyridinyl, quinazolinyl, {[(methylphenyl)sulfonyl]amino}pyridinyl, [(phenylsulfonyl)amino]pyridinyl, [(dimethylpyrazolyl)ethyl]triazolyl, (morpholinylethyl)triazolyl, [(dimethylisoxazolyl)ethyl]triazolyl, (fluoropyridinyl)triazolyl, pyridinylphenyl, indazolyl, [(acetylamino)methyl]phenyl, [(benzylamino)carbonyl]phenyl, (aminocarbonyl)phenyl, [(furylmethyl)amino]carbonylphenyl, {[(ethylamino)carbonyl]amino}(methoxy)phenyl, (fluoro)[(phenylamino)carbonyl]phenyl, (methoxy)[(benzylamino)sulfonyl]phenyl and (pyridinylmethyl)pyrazolyl.
Specific R1 groups are hydrogen, cyano, methoxy, iodine, chlorine, bromine, pyridin-3-yl, cyclopropyl, 5-methyl-1-phenyl-1H-pyrazol-4-yl, 5 methyl-1-pyridin-2-yl-1H-pyrazol-4-yl, trimethylsilyl, 4-methoxyphenyl, hydroxy, 1-methyl-1H-imidazol-5-yl, 3-(acetylamino)phenyl, methylsulfonyl, 1-(tert-butoxycarbonyl)pyrrolidin-3-yl, 1-(tert-butoxycarbonyl)pyrrolidin-2-yl, pyridin-4-yl, 6-aminopyridin-3-yl, 2-aminopyridin-4-yl, 1-(tert-butoxycarbonyl)azetidin-3-yl, 1-(tert-butoxycarbonyl)piperidin-4-yl, 6-pyrrolidin-1-ylpyridin-3-yl, 3-acetylphenyl, 3-hydroxyphenyl, 3,5-dimethyl-1H-pyrazol-4-yl, 3,5-dimethylisoxazol-4-yl, 1-[(dimethylamino)sulfonyl]-1H-imidazol-4-yl, 1-methyl-1H-pyrazol-4-yl, 2-(aminocarbonyl)pyridin-4-yl, 6-methoxypyridin-3-yl, 6-hydroxyypyridin-3-yl, 2-chloropyridin-4-yl, 1-methyl-1H-imidazol-4-yl, 6-fluoropyridin-6-yl, 2-amino-1,3-thiazol-5-yl, 2-(acetylamino)pyridin-4-yl, 1,3-thiazol-2-yl, 5-methylisoxazol-4-yl, 1H-imidazol-4-yl, 1,3,5-trimethyl-1H-pyrazol-4-yl, 1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl, 1H-pyrazol-4-yl, 1-benzyl-1H-pyrazol-4-yl, azetidin-3-yl, 2-methyl-1H-imidazol-4-yl, pyrrolidin-3-yl, 5-(methoxycarbonyl)-1H-pyrrol-3-yl, imidazo[1,2-a]pyridin-3-yl, 4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl, 3-amino-1-methyl-1H-pyrazol-4-yl, imidazo[1,2-a]pyrazin-3-yl, 5-tertbutyl-1,3,4-thiadiazol-2-yl, 5-methyl-1,3,4-thiadiazol-2-yl, 5-cyclopropyl-1,3,4-thiadiazol-2-yl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-3-yl, 5-ethyl-1,3,4-thiadiazol-2-yl, 7-(tertbutoxycarbonyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-3(8H)-yl, 2-(acetylamino)-1,3-thiazol-5-yl, 6-methylimidazo[1,2-a]pyridin-3-yl, 1-methyl-2-phenyl-1H-imidazol-5-yl, 1-(2-fluorophenyl)-5-methyl-1H-pyrazol-4-yl, 1-(4-chlorophenyl)-5-methyl-1H-pyrazol-4-yl, 7-methylimidazo[1,2-a]pyridin-3-yl, 1-(4-tertbutylphenyl)-5-methyl-1H-pyrazol-4-yl, 1-(4-fluorophenyl)-5-methyl-1H-pyrazol-4-yl, 1-(2-chlorophenyl)-5-methyl-1H-pyrazol-4-yl, 8-methylimidazo[1,2-a]pyridin-3-yl, 1,2-dimethyl-1H-imidazol-5-yl, 1-phenyl-1H-pyrazol-4-yl, 1,5-dimethyl-1H-pyrazol-4-yl, 5-methyl-1-(3-methylphenyl)-1H-pyrazol-4-yl, 1-(3-methoxyphenyl)-5-methyl-1H-pyrazol-4-yl, 5-methyl-1-pyridin-3-yl-1H-pyrazol-4-yl, 2,7-diazaspiro[3.5]non-2-yl, 2,6-diazaspiro[3.3]hept-2-yl, pyrrolidin-1-yl, 2-carboxy-3-methylphenyl, 3-(trifluoromethyl)pyridin-4-yl, 3-bromopyridin-4-yl, 6-cyanopyridin-3-yl, imidazo[1,2-a]pyridin-3-yl, 3-(acetylamino)phenyl, pyrazin-2-yl, pyridazin-3-yl, 2-hydroxypyridin-3-yl, 4-aminophenyl, 1H-indazol-5-yl, 1H-benzimidazol-5-yl, 1,3-dihydro-2-oxo-2H-benzimidazol-5-yl, 1H-indol-6-yl, 4-methylpyridin-3-yl, 2-methylpyridin-3-yl, pyrimidin-5-yl, 6-methylpyridin-3-yl, 1,2,3-thiadiazol-5-yl, phenyl, morpholin-4-yl, 2,6-diazaspiro[3.5]non-2-yl, pyridin-2-yl, dimethylamino, 5-bromo-1-benzothien-2-yl, 2,3-dimethylpyridin-4-yl, 4-(acetylamino)phenyl, methyl, 1-benzylpyrrolidin-3-yl, 1-(hydroxymethyl)cyclopentyl, 5-(ethylsulfonyl)-2-hydroxyphenyl, 4-aminopyridin-2-yl, 6-methoxyquinolin-4-yl, 3-cyclopropyl-1-methyl-1H-pyrazol-5-yl, 5-(aminocarbonyl)-1-ethyl-1H-pyrazol-4-yl, 1-(trifluoroacetyl)azetidin-3-yl, ethyl, cyclopentyl, 4-(trifluoromethyl)phenyl, 4-chlorophenyl, thien-3-yl, 4-cyanophenyl, 4-fluorophenyl, 2-methylphenyl, 2-chlorophenyl, 2-fluorophenyl, 3-chlorophenyl, 3-fluorophenyl, 3-methylphenyl, 1-methyl-1H-imidazol-5-yl, thien-2-yl, 2-methoxyphenyl, 2,4-difluorophenyl, amino, 3-aminophenyl, 3-[(methylsulfonyl)amino]phenyl, 5-({[(1S,2R)-2-aminocyclohexyl]amino}carbonyl)thien-3-yl, 4-(methoxycarbonyl)phenyl, 4-(aminocarbonyl)phenyl, 1-[(aminocarbonyl)methyl]-1H-pyrazol-4-yl, 5-(methoxycarbonyl)thien-3-yl, 5-carboxythien-3-yl, 5-{[(1S,2R)-2-aminocyclohexyl]amino}carbonylthien-3-yl, 5-(aminocarbonyl)thien-3-yl, 1H-pyrrol-3-yl, 5-[(2,2,2-trifluoroethyl)amino]carbonylthien-3-yl, 5-{[(1S,2S)-2-aminocyclohexyl]amino}carbonylthien-3-yl, 5-[(2-aminoethyl)amino]carbonylthien-3-yl, 5-(piperazin-1-ylcarbonyl)thien-3-yl, 5-({[3-(2-oxopyrrolidin-1-yl)propyl]amino}carbonyl)thien-3-yl, 3-isothiazol-4-yl, 5-(aminocarbonyl)-1H-pyrrol-3-yl, 3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl, 5-ethyl-1-phenyl-1H-pyrazol-4-yl, 5-cyclopropyl-1-phenyl-1H-pyrazol-4-yl, 5-methyl-1-(2-thienyl)-1H-pyrazol-4-yl, 1-methyl-2-(2-thienyl)-1H-imidazol-5-yl, 2-[(3-methoxyphenyl)sulfonylamino]pyridin-4-yl, 1-{[(phenylamino)carbonyl]amino}pyridin-4-yl, 1-[(pyridin-3-ylmethyl)methoxycarbonyl]azetidin-3-yl, 1-(3-chlorophenyl)-5-methyl-1H-pyrazol-4-yl, 1-(3-fluorophenyl)-5-methyl-1H-pyrazol-4-yl, 1-(2-methoxyphenyl)-5-methyl-1H-pyrazol-4-yl, 1-(4,5-dimethyl-1,3-thiazol-2-yl)-5-methyl-1H-pyrazol-4-yl, 1-(2,6-dimethylphenyl)-5-methyl-1H-pyrazol-4-yl, 1-(2-fluorophenyl)-3-methyl-1H-pyrazol-4-yl, 1-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl, 3-methyl-1-phenyl-1H-pyrazol-4-yl, 5-tert-butyl-1-phenyl-1H-pyrazol-4-yl, 5-isopropyl-1-phenyl-1H-pyrazol-4-yl, 5-cyclobutyl-1-phenyl-1H-pyrazol-4-yl, 5-methyl-1-(3-thienyl)-1H-pyrazol-4-yl, 5-methyl-1-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazol-4-yl, pyrrolidin-3-yl, 5-pyridin-3-yl-1,3,4-thiadiazol-2-yl, 1-methyl-2-(3-thienyl)-1H-imidazol-5-yl, 2-(2-methoxyethyl)-1-methyl-1H-imidazol-5-yl, 2-isopropyl-1-methyl-1H-imidazol-5-yl, 2-cyclobutyl-1-methyl-1H-imidazol-5-yl, 1-methyl-2-(tetrahydrofuran-3-yl)-1H-imidazol-5-yl, 2-(3-furyl)-1-methyl-1H-imidazol-5-yl, 2-cyclopentyl-1-methyl-1H-imidazol-5-yl, 2-(fluoromethyl)-1-methyl-1H-imidazol-5-yl, 1-methyl-2-(5-methylisoxazol-3-yl)-1H-imidazol-5-yl, 2-(2-furyl)-1-methyl-1H-imidazol-5-yl, 1-methyl-2-pyridin-2-yl-1H-imidazol-5-yl, 1-methyl-2-(4-methyl-1,3-thiazol-2-yl)-1H-imidazol-5-yl, 1-methyl-2-(2-methyl-1,3-thiazol-4-yl)-1H-imidazol-5-yl, 1,5-naphthyridin-4-yl, 1,8-naphthyridin-4-yl, quinazolin-4-yl, 2-{[(2-methylphenyl)sulfonyl]amino}pyridin-4-yl, 2-[(phenylsulfonyl)amino]pyridin-4-yl, 1-[2-(3,5-dimethyl-1H-pyrazol-4-yl)ethyl]-1H-1,2,3-triazol-4-yl, 1-(2-morpholin-4-ylethyl)-1H-1,2,3-triazol-4-yl, 1-[2-(3,5-dimethylisoxazol-4-yl)ethyl]-1H-1,2,3-triazol-4-yl, 1-(2-fluoropyridin-3-yl)-1H-1,2,3-triazol-4-yl, 4-pyridin-4-ylphenyl, 1H-indazol-5-yl, 4-[(acetylamino)methyl]phenyl, 4-[(benzylamino)carbonyl]phenyl, 4-(aminocarbonyl)phenyl, 4-pyridin-2-ylphenyl, 4-[(2-furylmethyl)amino]carbonylphenyl, 4-{[(ethylamino)carbonyl]amino}-3-methoxyphenyl, 3-fluoro-4-[(phenylamino)carbonyl]phenyl, 4-methoxy-3-[(benzylamino)sulfonyl]phenyl, 1-(pyridin-2-ylmethyl)-1H-pyrazol-4-yl and 4-pyridin-3-ylphenyl.
In an embodiment L2 is —O(CRaRb)d or —NRc)(C═O)—.
In an embodiment L2 is —O(CRaRb)d—. In another embodiment L2 is —NRc)(C═O)b—.
Particular L2 groups are —O—, —OCH2— and NH(C═O)—.
In an embodiment L2 is —O—.
In an embodiment R2 is C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1-alkoxy or a ring which is: C6-10aryl, C3-10cycloalkyl, azetidinyl, a 5, 6 or 7 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 atoms independently selected from N, O and S, a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S, or a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms; any of which rings being optionally substituted by one, two or three groups independently selected from Re.
In an embodiment R2 is methyl, tertbutoxy or a ring selected from: phenyl, piperidinyl, pyridinyl and pyrrolidinyl; any of which rings being optionally substituted by one, two or three groups independently selected from Re.
In an embodiment when R2 is a ring it is optionally substituted by one or two independently selected Re groups. In another embodiment the R1 ring is unsubstituted or monosubstituted.
In an embodiment Re is C1-6alkoxycarbonyl or C1-6alkylsulfonyl.
Specific Re groups are tertbutoxycarbonyl and methylsulfonyl.
Particular R2 groups are methyl, phenyl, piperidinyl, pyridinyl, (tertbutoxycarbonyl)piperidinyl, (methylsulfonyl)pyrrolidinyl and tertbutoxy.
Specific R2 groups are methyl, phenyl, piperidin-3-yl, pyridin-3-yl, pyridin-2-yl, 1-(tertbutoxycarbonyl)piperidin-3-yl, pyridin-4-yl, 1-(methylsulfonyl)pyrrolidin-3-yl and tertbutoxy.
In an embodiment L2R2 is methoxy.
In an embodiment when R3 is a ring it is optionally substituted by one or two independently selected groups. In another embodiment the R3 ring is unsubstituted or monosubstituted.
A specific R3 group is hydrogen.
In an embodiment L3 is a direct bond. In another embodiment L3 is —C≡C—.
In another embodiment L3 is —(HC═CH)e(CRaRb)d(NRc)c—.
In another embodiment L3 is —(HC═CH)e(CH2)d(NH)c—.
Specific L3 groups are a direct bond, —NH—, —(HC═CH)(CH2)NH—, —(HC═CH)—, —(HC═CH)(CH2)—, —(CH2)—, —(CH2)2 and —(C≡C)—.
In an embodiment R4 is hydrogen, halogen, C1-6alkyl, haloC1-6 alkyl, C1-6alkoxy, haloC1-alkoxy, C1-6alkoxycarbonyl or a ring which is: C6-10aryl, C6-10arylC1-6alkyl, C3-10cycloalkyl, azetidinyl, a 5, 6 or 7 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 atoms independently selected from N, O and S, a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S or a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms; any of which rings being optionally substituted by one, two or three groups independently selected from L5-Rf.
In an embodiment R4 is bromine, methoxy, hydrogen, butoxycarbonyl, ethyl or a ring selected from: pyrazolyl, thienyl, pyridinyl, phenyl, furyl, morpholinyl, cyclopropyl, pyrimidinyl and dioxanyl; any of which rings being optionally substituted by one, two or three groups independently selected from L5-Rf.
In an embodiment when R4 is a ring it is optionally substituted by one or two independently selected groups. In another embodiment the R4 ring is unsubstituted or monosubstituted.
In an embodiment L5 is a direct bond.
In an embodiment L5 is —(C═O)b(NRc)c(C═O)b(CRaRb)d—.
In an embodiment L5 is a direct bond, —(C═O)N(Rc)(CRaRb)—, —(C═O)—, —N(Rc)(C═O)—, —(C═O)N(Rc)—, —(C═O)N(Rc)(CRaRd)2— or —(CRaRb)3—.
Specific L5 groups are a direct bond, —(C═O)NH(CH2)—, —(C═O)—, —NH(C═O)—, —(C═O)NH—, —(C═O)NH(CH2)2— and —CH2CHFCH2—.
In an embodiment Rf is hydroxy, halogen, C1-6alkyl, haloC1-6alkyl, C1-6alkoxy, haloC1-6alkoxy, amino, (C1-6alkyl)amino, di(C1-6alkyl)amino or a ring which is: C6-10aryl, C3-10cycloalkyl, azetidinyl, a 5, 6 or 7 membered saturated or partially saturated heterocyclic ring containing 1, 2 or 3 atoms independently selected from N, O and S, a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, and S, not more than one heteroatom of which is O or S or a 6 membered heteroaromatic ring containing 1, 2 or 3 N atoms; any of which rings being optionally substituted by one, two or three groups independently selected from hydroxy, oxo, cyano, halogen, C1-6alkyl, C2-10alkenyl, haloC1-6alkyl, hydroxyC1-6alkyl, C1-6alkylcarbonyl, C1-6alkoxy, haloC1-alkoxy, C1-6alkoxycarbonyl, carboxy, nitro, amino, (C1-6alkyl)amino and di(C1-6alkyl)amino.
In an embodiment Rf is methyl, methoxy, hydroxyl, amino, dimethylamino, or a ring selected from: furyl, morpholinyl, piperazinyl, oxaazabicyclo[2.2.1]heptyl, piperidinyl, pyridinyl and phenyl, any of which rings may be optionally substituted by one, two or three groups independently selected from hydroxy, oxo, cyano, halogen, C1-6alkyl, C2-10alkenyl, haloC1-6alkyl, hydroxyC1-6alkyl, C1-6alkylcarbonyl, C1-6alkoxy, haloC1-alkoxy, C1-6alkoxycarbonyl, carboxy, nitro, amino, (C1-6alkyl)amino and di(C1-6alkyl)amino.
In an embodiment when Rf is a ring it is optionally substituted by one or two independently selected groups. In another embodiment the Rf ring is unsubstituted or monosubstituted.
In an embodiment the optional substituents on the Rf ring are selected from C1-6alkyl and C1-6alkoxy.
Particular optional substituents on the Rf ring are methyl and methoxy.
Particular Rf groups are methyl, furyl, morpholinyl, methylpiperazinyl, dimethylamino, oxaazabicyclo[2.2.1]heptyl, methoxypiperidinyl, pyridinyl, phenyl, methoxy, amino and hydroxy.
Specific Rf groups are methyl, 2-furyl, morpholin-4-yl, 4-methylpiperazin-1-yl, dimethylamino, 2-oxa-5-azabicyclo[2.2.1]hept-5-yl, 4-methoxypiperidin-1-yl, pyridin-4-yl, phenyl, methoxy, amino and hydroxy.
Particular R4 groups are bromine, methoxy, hydrogen, methylpyrazolyl, methylthienyl, pyridinyl, phenyl, {[(furylmethyl)amino]carbonyl}phenyl, (morpholinylcarbonyl)phenyl, morpholinylpyridinyl, (methylpiperazinyl)pyridinyl, (dimethylamino)pyridinyl, furyl, [(morpholinylcarbonyl)amino]phenyl, (oxaazabicyclo[2.2.1]heptylcarbonyl)phenyl, [(methoxypiperidinyl)carbonyl]phenyl, pyridinylphenyl, [(phenylamino)carbonyl]phenyl, {[(methoxyethyl)amino]carbonyl}phenyl, aminopyridinyl, hydroxypyridinyl, morpholinyl, (fluoropropanol)pyrazolyl, cyclopropyl, pyrazolyl, pyrimidinyl, tert-butoxycarbonyl, ethyl, fluorophenyl, hydroxydimethyldioxanyl and aminopyrimidinyl.
Specific R4 groups are bromine, methoxy, hydrogen, 1-methyl-1H-pyrazol-4-yl, 4-methylthien-3-yl, pyridin-4-yl, phenyl, 4-{[(2-furylmethyl)amino]carbonyl}phenyl, 4-(morpholin-4-ylcarbonyl)phenyl, 6-morpholin-4-ylpyridin-3-yl, 2-(4-methylpiperazin-1-yl)pyridin-4-yl, 6-(dimethylamino)pyridin-3-yl, 3-furyl, 4-[(morpholin-4-ylcarbonyl)amino]phenyl, 4-(2-oxa-5-azabicyclo[2.2.1]hept-5-ylcarbony)phenyl, 4-[(4-methoxypiperidin-1-yl)carbonyl]phenyl, 4-pyridin-4-ylphenyl, 4-[(phenylamino)carbonyl]phenyl, 4-{[(2-methoxyethyl)amino]carbonyl}phenyl, 6-aminopyridin-3-yl, 6-hydroxypyridin-3-yl, morpholin-4-yl,1-(2-fluoropropan-3-ol)-1H-pyrazol-4-yl, cyclopropyl, 1H-pyrazol-5-yl, pyridin-3-yl, pyrimidin-5-yl, tert-butoxycarbonyl, ethyl, 4-fluorophenyl, 5-hydroxy-2,2-dimethyl-1,3-dioxan-5-yl and 2-aminopyrimidin-5-yl.
In an embodiment L3R4 is a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S or a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms; any of which rings being optionally substituted by one, two or three groups independently selected from L5-Rf.
In an embodiment L3R4 is 1-methyl-1H-pyrazol-4-yl.
In an embodiment R5 is hydrogen, C1-6alkyl or amino.
Particular R5 groups are amino, hydrogen and methyl.
In an embodiment each of R3 and R5 is hydrogen.
In an embodiment each of R3 and R5 is hydrogen and L2R2 is methoxy.
In an embodiment:
R1 is hydrogen, cyano, methoxy, iodine, chlorine, bromine, trimethylsilyl, hydroxy, methylsulfonyl, dimethylamino, methyl, ethyl, amino or a ring selected from: pyridinyl, cyclopropyl, pyrazolyl, phenyl, imidazolyl, pyrrolidinyl, azetidinyl, piperidinyl, isoxazolyl, thiazolyl, pyrrolyl, imidazopyridinyl, pyrazolopyridinyl, imidazopyrazinyl, thiadiazolyl, tetrahydroimidazopyridinyl, dihydrotriazolopyrazinyl, diazaspiro[3.5]nonyl, diazaspiro[3.3]heptyl, pyrazinyl, pyridazinyl, indazolyl, benzimidazolyl, dihydrobenzimidazolyl, indolyl, pyrimidinyl, morpholinyl, benzothienyl, cyclopentyl, quinolinyl, thienyl, isothiazolyl, naphthyridinyl, quinazolinyl and triazolyl; any of which rings being optionally substituted by one, two or three groups independently selected from L4-Rd;
R2 is methyl, tertbutoxy or a ring selected from: phenyl, piperidinyl, pyridinyl and pyrrolidinyl; any of which rings being optionally substituted by one, two or three groups independently selected from Re;
R3 is hydrogen;
R4 is bromine, methoxy, hydrogen, butoxycarbonyl, ethyl or a ring selected from: pyrazolyl, thienyl, pyridinyl, phenyl, furyl, morpholinyl, cyclopropyl, pyrimidinyl and dioxanyl; any of which rings being optionally substituted by one, two or three groups independently selected from L5-Rf; and
R5 is hydrogen, C1-6alkyl or amino.
In another embodiment:
R1 is hydrogen, cyano, methoxy, iodine, chlorine, bromine, trimethylsilyl, hydroxy, methylsulfonyl, dimethylamino, methyl, ethyl, amino or a ring selected from: pyridinyl, cyclopropyl, pyrazolyl, phenyl, imidazolyl, pyrrolidinyl, azetidinyl, piperidinyl, isoxazolyl, thiazolyl, pyrrolyl, imidazopyridinyl, pyrazolopyridinyl, imidazopyrazinyl, thiadiazolyl, tetrahydroimidazopyridinyl, dihydrotriazolopyrazinyl, diazaspiro[3.5]nonyl, diazaspiro[3.3]heptyl, pyrazinyl, pyridazinyl, indazolyl, benzimidazolyl, dihydrobenzimidazolyl, indolyl, pyrimidinyl, morpholinyl, benzothienyl, cyclopentyl, quinolinyl, thienyl, isothiazolyl, naphthyridinyl, quinazolinyl and triazolyl; any of which rings being optionally substituted by one, two or three groups independently selected from L4-Rd; and
R4 is bromine, methoxy, hydrogen, butoxycarbonyl, ethyl or a ring selected from: pyrazolyl, thienyl, pyridinyl, phenyl, furyl, morpholinyl, cyclopropyl, pyrimidinyl and dioxanyl; any of which rings being optionally substituted by one, two or three groups independently selected from L5-Rf.
In an embodiment each one of Ra and Rb is independently selected from hydrogen, halogen, hydroxy and C1-6alkyl.
In another embodiment each one of Ra and Rb is independently selected from hydrogen, methyl, fluorine and hydroxy. In another embodiment each one of Ra and Rb is hydrogen.
In an embodiment each Rc is independently selected from hydrogen and methyl.
In an embodiment each Rx is independently selected from hydrogen and methyl.
The present invention also provides compounds of formula II:
wherein:
L1, L2, L3, R1, R2, R3, R4 and R5 are as defined above;
or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.
The present invention also provides compounds of formula III:
wherein:
L1, L2, L3, R1, R2, R3, R4 and R5 are as defined above;
or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.
The present invention also provides compounds of formula IV:
wherein:
d, L1, L3, R1, R2, R3, R4, R5, Ra, Rb, X, Y and Z are as defined above;
or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.
The present invention also provides compounds of formula V:
wherein:
R4 is a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S or a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms; any of which rings being optionally substituted by one, two or three groups independently selected from L5-Rf;
d, L1, L5, R1, R2, Ra, Rb, Rf, X, Y and Z are as defined above;
or a pharmaceutically acceptable stereoisomer or tautomer thereof.
The present invention also provides compounds of formula VI:
wherein:
d, L3, R1, R2, R4, Ra, Rb, X, Y and Z are as defined above;
or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.
The present invention also provides compounds of formula VII:
wherein:
L3, R1 and R4 are as defined above;
or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.
The present invention also provides compounds of formula VIII:
wherein:
L1 is —(C≡C)a(C═O)b(NRc)c(CRaRb)d(NRc)c(C═O)b;
R4 is a 5 membered heteroaromatic ring containing 1, 2, 3 or 4 heteroatoms independently selected from N, O and S, not more than one heteroatom of which is O or S or a 6 membered heteroaromatic ring containing 1, 2 or 3 nitrogen atoms; any of which rings being optionally substituted by one, two or three groups independently selected from L5-Rf;
a, b, c, d, L5, R1, Ra, Rb, Re and Rf are as defined above;
or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.
The present invention also provides compounds of formula IX:
wherein:
d, L3, R1, R4, Ra, Rb and Rc are as defined above;
or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.
The present invention also provides compounds of formula X:
wherein:
d, L3, R1, R4, Ra, Rb and Rc are as defined above;
or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.
The present invention also provides compounds of formula XI:
wherein:
d, R1, R4, Ra, Rb and Rc are as defined above;
or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.
The present invention also provides compounds of formula XII:
wherein:
b, L1, L3, R1, R2, R4 and Rc are as defined above;
or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.
The present invention also provides compounds of formula XIII:
wherein:
b, d, L3, R1, R2, R4, Ra, Rb and Rc are as defined above;
or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.
The present invention also provides compounds of formula XIV:
wherein:
d, R1, R4, Ra and Rb are as defined above;
or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.
The present invention also provides compounds of formula XV:
wherein:
d, L1, L3, R1, R2, R3, R4, Ra and Rb are as defined above;
or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.
The present invention also provides compounds of formula XVI:
wherein:
L1, R1 and R4 are as defined above;
or a pharmaceutically acceptable salt, stereoisomer or tautomer thereof.
The preferred identities with reference to formulae II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV and XVI are as defined previously for formula I mutatis mutandis.
The present invention also includes within its scope N-oxides of the compounds of formula I above. In general, such N-oxides may be formed on any available nitrogen atom. The N-oxides may be formed by conventional means, such as reating the compound of formula I with oxone in the presence of wet alumina.
The present invention includes within its scope prodrugs of the compounds of formula I above. In general, such prodrugs will be functional derivatives of the compounds of formula I which are readily convertible in vivo into the required compound of formula I. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.
A prodrug may be a pharmacologically inactive derivative of a biologically active substance (the “parent drug” or “parent molecule”) that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule. The transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality.
The present invention includes within its scope solvates of the compounds of formula I and salts thereof, for example, hydrates.
The compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (as described in: E. L. Eliel and S. H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190), and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers and mixtures thereof, including optical isomers, all such stereoisomers being included in the present invention. In addition, the compounds disclosed herein may exist as tautomers and both tautomeric forms are intended to be encompassed by the scope of the invention, even though only one tautomeric structure is depicted. If the ring system is bicyclic, it is intended that the bond be attached to any of the suitable atoms on either ring of the bicyclic moiety.
The compounds may exist in different isomeric forms, all of which are encompassed by the present invention.
The compounds may exist in a number of different polymorphic forms.
When any variable (e.g. R2, etc.) occurs more than one time in any constituent, its definition on each occurrence is independent at every other occurrence. Also, combinations of substituents and variables are permissible only if such combinations result in stable compounds. Lines drawn into the ring systems from substituents represent that the indicated bond may be attached to any of the substitutable ring atoms.
It is understood that one or more silicon (Si) atoms can be incorporated into the compounds of the instant invention in place of one or more carbon atoms by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials. Carbon and silicon differ in their covalent radius leading to differences in bond distance and the steric arrangement when comparing analogous C-element and Si-element bonds. These differences lead to subtle changes in the size and shape of silicon-containing compounds when compared to carbon. One of ordinary skill in the art would understand that size and shape differences can lead to subtle or dramatic changes in potency, solubility, lack of off target activity, packaging properties, and so on. (Diass, J. O. et al. Organometallics (2006) 5:1188-1198; Showell, G. A. et al. Bioorganic & Medicinal Chemistry Letters (2006) 16:2555-2558).
In an embodiment one or more hydrogen atoms in the compounds of the present invention may be replaced by Deuterium.
It is understood that substituents and substitution patterns on the compounds of the instant invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results. The phrase “optionally substituted” should be taken to be equivalent to the phrase “unsubstituted or substituted with one or more substituents” and in such cases the preferred embodiment will have from zero to three substituents. More particularly, there are zero to two substituents. A substituent on a saturated, partially saturated or unsaturated heterocycle can be attached at any substitutable position.
As used herein, “alkyl” is intended to include both branched, straight-chain and cyclic saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, “C1-6alkyl” is defined to include groups having 1, 2, 3, 4, 5 or 6 carbons in a linear, branched or cyclic arrangement. For example, “C1-6alkyl” specifically includes methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, cyclopropylmethyl, cyclobutylmethyl and so on. Preferred alkyl groups are methyl ethyl and cycloalkylmethyl, especially methyl and ethyl. The term “cycloalkyl” means a monocyclic, bicyclic or polycyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, “C3-10cycloalkyl” is defined to include groups having 3, 4, 5, 6, 7, 8, 9 or 10 carbons and includes cyclopropyl, cyclopropylmethyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and so on. In an embodiment of the invention the term “cycloalkyl” includes the groups described immediately above and further includes monocyclic unsaturated aliphatic hydrocarbon groups. For example, “cycloalkyl” as defined in this embodiment includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, cyclopentenyl, cyclobutenyl, 7,7-dimethylbicyclo[2.2.1]heptyl and so on. Preferred cycloalkyl groups are cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl and cyclohexyl.
As used herein, the term “C2-6alkenyl” refers to a non-aromatic hydrocarbon radical, straight or branched, containing from 2 to 6 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non-aromatic carbon-carbon double bonds may be present. Alkenyl groups include ethenyl, propenyl, butenyl and 2-methylbutenyl. Preferred alkenyl groups include ethenyl and propenyl.
As used herein, the term “C2-6alkynyl” refers to a hydrocarbon radical straight or branched, containing from 2 to 6 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be present. Alkynyl groups include ethynyl, propynyl, butynyl, 3-methylbutynyl and so on. Preferred alkynyl groups include ethynyl and propynyl
“Alkoxy” represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge. “Alkoxy” therefore encompasses the definitions of alkyl above. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy. The preferred alkoxy groups are methoxy and ethoxy. The term ‘C6-10aryloxy’ can be construed analogously, and an example of this group is phenoxy.
The terms “haloC1-6alkyl” and “haloC1-6alkoxy” mean a C1-6alkyl or C1-6alkoxy group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by halogen atoms, especially fluorine or chlorine atoms. Preferred are fluoroC1-6alkyl and fluoroC1-6alkoxy groups, in particular fluoroC1-3alkyl and fluoroC1-3alkoxy groups, for example, CF3, CHF2, CH2F, CH2CH2F, CH2CHF2, CH2CF3, OCF3, OCHF2, OCH2F, OCH2CH2F, OCH2CHF2 or OCH2CF3, and most especially CF3, OCF3 and OCHF2.
As used herein, the term “hydroxyC1-6alkyl” means a C1-6alkyl group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by hydroxy groups. Preferred are CH2OH, CH2CHOH and CHOHCH3.
The term “C1-6alkylcarbonyl” or “C1-6alkoxycarbonyl” denotes a C1-6alkyl or C1-6alkoxy radical, respectively, attached via a carbonyl (C═O) radical. Suitable examples of C1-6alkylcarbonyl groups include methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl and tert-butylcarbonyl. Examples of C1-6alkoxycarbonyl include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl and tert-butoxycarbonyl. The term ‘C6-10arylcarbonyl’ can be construed analogously, and an example of this group is benzoyl.
The rings present in the compounds of this invention may be monocyclic or multicyclic, particularly bicyclic. The multicyclic rings may be fused or spiro linked.
As used herein, “C6-10aryl” is intended to mean any stable monocyclic or bicyclic carbon ring of 6 to 10 atoms, wherein at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl and tetrahydrobenzo[7]annulene. The preferred aryl group is phenyl or naphthyl, especially phenyl.
7-15 membered heterocycles include 7, 8, 9, 10, 11, 12, 13, 14 and 15 membered heterocycles.
Examples of particular heterocycles of this invention are benzimidazolyl, benzofurandionyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothienyl, benzoxazolyl, benzoxazolonyl, benzothiazolyl, benzothiadiazolyl, benzodioxolyl, benzoxadiazolyl, benzoisoxazolyl, benzoisothiazolyl, chromenyl, chromanyl, isochromanyl, carbazolyl, carbolinyl, cinnolinyl, epoxidyl, furyl, furazanyl, imidazolyl, indolinyl, indolyl, indolizinyl, indolinyl, isoindolinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazolinyl, isoxazolinyl, oxetanyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridinyl, pyrimidinyl, triazinyl, tetrazinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, quinolizinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroisoquinolinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidyl, pyridin-2-onyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrrolinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydroisoquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, dihydroisochromenyl, dihydrochromenyl, dihydroimidazolonyl, dihydrotriazolonyl, dihydrobenzodioxinyl, dihydrothiazolopyrimidinyl, dihydroimidazopyrazinyl, methylenedioxybenzoyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydroquinolinyl, thiazolidinonyl, imidazolonyl, isoindolinonyl, octahydroquinolizinyl, octahydroisoindolyl, imidazopyridinyl, azabicycloheptanyl, chromenonyl, triazolopyrimidinyl, dihydrobenzoxazinyl, thiazolotriazolyl, azoniabicycloheptanyl, azoniabicyclooctanyl, phthalazinyl, naphthyridinyl, quinazolinyl, pteridinyl, dihydroquinazolinyl, dihydrophthalazinyl, benzisoxazolyl, tetrahydronaphthyridinyl, dibenzo[b,d]furanyl, dihydrobenzothiazolyl, imidazothiazolyl, tetrahydroindazolyl, tetrahydrobenzothienyl, hexahydronaphthyridinyl, tetrahydroimidazopyridinyl, tetrahydroimidazopyrazinyl, pyrrolopyridinyl, azoniaspiro[5.5]undecanyl, azepanyl, octahydroindolizinyl, 1′2′-dihydrospirocyclohexane-1,3′-indolyl, azoniabicyclo[3.1.0]hexanyl, diazoniaspiro[4.4]nonanyl, hexahydropyrrolo[3,4-b]pyrrolyl, oxaazoniabicyclo[2.2.1]heptanyl, diazoniaspriro[5.5]undecanyl, diazoniaspiro[3.3]heptanyl, diazoniaspiro[3.5]nonanyl, diazoniaspiro[4.5]decanyl, octahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydrocyclopenta[c]pyrrolyl, dihydroindolyl, azoniaspiro[4.5]decanyl, diazoniabicyclo[2.2.2]octanyl, diazoniabicyclo[2.2.1]heptanyl, diazoniabicyclo[3.2.1]octanyl, diazoniabicyclo[2.2.1]heptanyl, azoniabicyclo[3.1.0]hexanyl, tetrahydrothiophenyl, oxaazoniaspiro[4.5]decanyl, oxazepanyl and N-oxides thereof. Attachment of a heterocyclyl substituent can occur via a carbon atom or via a heteroatom.
Preferred 5 or 6 membered saturated or partially saturated hetereocycles are pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuran, thiomorpholinyl, dihydroimidazolyl and tetrahydropyranyl.
A preferred 7 membered saturated heterocycle is diazepanyl, azepanyl and oxazepanyl.
Preferred 5 membered heteroaromatic rings are thienyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazolyl, thiadiazolyl, oxazolyl, oxadiazolyl, triazolyl, tetrazolyl, furyl and pyrrolyl.
Preferred 6 membered heteroaromatic rings are pyridinyl, pyrimidinyl, pyridazinyl and pyrazinyl.
Preferred 7-15 membered partially saturated or unsaturated heterocyclic rings are tetrahydroquinolinyl, quinolinyl, indolyl, imidazopyridinyl, benzothiazolyl, quinoxalinyl, benzothiadiazolyl, benzoxazolyl, dihydrobenzodioxinyl, benzotriazolyl, benzodioxolyl, dihydroisoindolyl, dihydroindolyl, tetrahydroisoquinolinyl, isoquinolinyl, benzoisothiazolyl, dihydroimidazopyrazinyl, benzothienyl, benzoxadiazolyl, thiazolotriazolyl, dihydrothiazolopyrimidinyl, dihydrobenzoxazinyl, dihydrobenzofuranyl, benzimidazolyl, benzofuranyl, dihydrobenzoxazolyl, dihydroquinazolinyl, dihydrophthalazinyl, indazolyl, benzisoxazolyl, tetrahydronaphthyridinyl, triazolopyrimidinyl, dibenzo[b,d]furanyl, naphthyridinyl, dihydroquinolinyl, dihydroisochromenyl, dihydrochromenyl, dihydrobenzothiazolyl, imidazothiazolyl, tetrahydroindazolyl, tetrahydrobenzothienyl, hexahydronaphthyridinyl, tetrahydroimidazopyridinyl, tetrahydroimidazopyrazinyl, pyrrolopyridinyl, quinazolinyl, indolizinyl, azoniaspiro[5.5]undecanyl, azepanyl, octahydroindolizinyl, 1′2′-dihydrospirocyclohexane-1,3′-indolyl, octahydroisoindolyl, azoniabicyclo[3.1.0]hexanyl, diazoniaspiro[4.4]nonanyl, hexahydropyrrolo[3,4-b]pyrrolyl, oxaazoniabicyclo[2.2.1]heptanyl, diazoniaspriro[5.5]undecanyl, diazoniaspiro[3.3]heptanyl, diazoniaspiro[3.5]nonanyl, diazoniaspiro[4.5]decanyl, octahydropyrrolo[3,4-c]pyrrolyl, octahydropyrrolo[3,4-b]pyrrolyl, octahydrocyclopenta[c]pyrrolyl, dihydroindolyl, azoniaspiro[4.5]decanyl, diazoniabicyclo[2.2.2]octanyl, diazoniabicyclo[2.2.1]heptanyl, diazoniabicyclo[3.2.1]octanyl, diazoniabicyclo[2.2.1]heptanyl, azoniabicyclo[3.1.0]hexanyl, tetrahydrothiophenyl, oxaazoniaspiro[4.5]decanyl and oxazepanyl.
As used herein, the term “halogen” refers to fluorine, chlorine, bromine and iodine, of which fluorine and chlorine are preferred.
Particular compounds within the scope of the present invention are:    Compound 1-1